Michelena, Héctor I.

Background: Calcific aortic valve stenosis (CAVS) is characterized by the progressive accrual of aortic valvular calcium (AVC), resulting in impaired valvular compliance and mechanics and impaired cardiac function leading to heart failure (HF). In a phase 2 trial of 23 patients with moderate CAVS, ataciguat (ATA), a soluble guanylate cyclase activator, relative to placebo slowed the deposition of AVC, decreases in aortic valve area (AVA; by continuity equation), and increases in diastolic dysfunction and left ventricular (LV) mass. ATA may have other favorable effects on ventricular, valvular, and/or vascular pathophysiology relevant to patients with CAVS. Hypothesis: We hypothesized that slowing the rate of AVC deposition is associated with improvements in valvular compliance and in measures of cardiac structure and function. Methods: A phase 2 study randomized patients with moderate CAVS 1:1 to receive ATA 200 mg/day or placebo for up to 12 months (NCT02481258). The primary endpoint was change in AVC assessed by cardiac CT, and measures of aortic valve function and cardiac structure and function were also assessed. AVA was calculated by the Modified Gorlin (Hakki) equation to additionally assess valvular compliance. Correlations between AVC, AVA, and other measures of cardiac structure and function were assessed by exploratory linear mixed models. Results: Changes in AVC from baseline were negatively correlated with changes in AVA (slope = −0.0002 [95% CI −0.0004, 0.0001]; Figure 1), such that patients with the least AVC deposition had minimal changes in AVA. Reciprocally, changes from baseline in AVA were positively correlated with changes in cardiac output (CO; slope = 0.16 [95% CI 0.13, 0.18]; Figure 2). Treatment with ATA, compared with placebo, was associated with improvements in systolic function. Changes in AVC deposition correlated with changes in CO (slope = −0.0007 [95% CI −0.0021, 0.0008]; Figure 3), and measured improvements in CO were generally more observed in patients with less of an increase in AVC, which were more frequently observed in those treated with ATA compared with placebo. Conclusions: These data suggest that slowing the rate of AVC deposition with ATA may result in improvements in CO through improved myocardial function and valvular compliance. Larger controlled trials are needed to assess such favorable myocardial/valvular effects that may help to preserve functional capacity and slow progression to HF.

Background Mitral valve prolapse (MVP) can be associated with ventricular arrhythmias (VA), but little is known about the relationship between VA and exercise in these patients. The aim of this study was to assess the occurrence and severity of VA during exercise tests in patients with MVP, and to explore the association between VA during exercise and the occurrence of arrhythmic events during follow-up. Methods In this multicentre study, 375 patients with MVP (58 (48–69) years, 53% male) who underwent a clinically indicated exercise test were included. Severity of VA during exercise was defined as: (1) no VA, (2) minor VA (premature ventricular contractions ≥5% or non-sustained ventricular tachycardia (nsVT) <120 beats per minute) and (3) major VA (nsVTs ≥120 beats per minute). Results During exercise test, 242 (65%) patients showed no VA, 88 (24%) minor VA and 45 (12%) major VA. Patients with minor and major VAs showed more often bileaflet prolapse and mitral annular disjunction (MAD) than patients with no VA (p<0.001). Over a median follow-up of 101 months (IQR 58–138 months), 35 patients (9%) developed a severe arrhythmic event, defined as sustained VA or ventricular fibrillation, implantation of an implantable cardioverter-defibrillator and VA ablation. At the Kaplan-Meier curve analysis, patients with major VA showed the worst arrhythmic event-free survival (log-rank p<0.001). On multivariable analysis, left ventricular end-systolic diameter, MAD and VA severity during exercise were independently associated with this outcome. Conclusions In patients with MVP, the occurrence of VA during exercise is associated with more advanced mitral valve abnormalities, including MAD, and with higher rates of severe arrhythmic events during follow-up. Performing an exercise test, combined with the clinical and echocardiographic assessments, may therefore offer important complementary information useful for patient management.

Background Left ventricular (LV) end‐systolic enlargement in severe degenerative mitral‐regurgitation (MR) is a class I surgical trigger. Whether it occurs disproportionately to less‐than‐severe MR due to mitral valve prolapse and is associated with mortality are unknown. We aimed to analyze prevalence and association with survival of disproportionate LV enlargement in less‐than‐severe MR. Methods A multicenter cohort international study enrolled 2848 consecutive patients (52% women, 69±16 years) with degenerative MR prospectively quantified and graded mild or moderate. Primary end point was survival under medical management. Secondary outcome was survival throughout follow‐up stratified by performance of early mitral surgery within 3 months postdiagnosis. Results Among LV remodeling parameters (abnormal end‐diastolic diameter, LV end‐systolic diameter [LVESD] absolute and indexed), LVESD ≥40 mm (present in 12.4%) was the sole independent associate of reduced survival (5‐year 70±3 versus 76±9%; P =0.009). LVESD ≥40 mm was independently linked to larger body surface area, effective regurgitant orifice, and left atrium, and to male sex and diabetes. With multivariable comprehensive adjustment, LVESD ≥40 mm (adjusted hazard ratio [aHR], 1.25 [95% CI, 1.005–1.53]; P =0.04) remained associated with excess mortality under medical management, even after adjustment for lowered ejection fraction (aHR, 1.49 [95% CI, 1.13–1.95]; P =0.004) and in all patient subsets. Among patients with moderate degenerative MR and LVESD ≥40 mm, 22% underwent mitral surgery within 3 months, which was associated with superior survival, even after comprehensive adjustment (aHR, 0.11 [95% CI, 0.005–0.51]; P =0.002). Conclusions Disproportionate LV enlargement in patients with less‐than‐severe degenerative MR is common, particularly with larger bodies, regurgitation, and overall cardiac remodeling. LVESD ≥40 mm is associated with worse survival independent of all baseline characteristics, even lowered ejection fraction, and represents a marker for risk stratification of patients who are generally not yet considered for medical or surgical/interventional treatment.

Background Atrial fibrillation (AF) impacts management decisions in valvular heart disease but its significance in patients with chronic aortic regurgitation (AR) is not well established. Objectives To evaluate the prevalence and prognostic role of AF in patients with chronic, haemodynamically significant AR. Methods Adults with chronic ≥moderate-to-severe AR, from March 2004 to April 2019, were retrospectively identified. Those with acute AR, moderate or worse other valve disease or prior valve surgery were excluded. Patients with AF were identified based on 12-lead ECGs, 1-lead ECGs (showing AF for ≥30 s), or episodes recorded by implanted cardiac devices. Primary outcome was all-cause mortality. Cox regression models were used to assess associations with mortality: model 1 adjusted for age, symptoms (New York Heart Association class II–IV), Charlson Comorbidity Index, left ventricle (LV) end-systolic volume index and AF; model 2 added left atrial volume index and model 3 further added systolic pulmonary artery pressure. Results Of the 1006 included patients (age 59±18 years; 822 (82%) men), 446 (46%) had hypertension and 364 (36%) had a bicuspid aortic valve. AF was present in 161 (16%) patients at the time of ≥moderate-to-severe AR diagnosis. During a median follow-up of 1.6 years (IQR 0.2–6.2), AF was associated with an increased mortality risk in univariate and in all three multivariable models (HR 1.61 (95% CI 1.07 to 2.43), HR 2.21 (95% CI 1.31 to 3.72) and HR 2.06 (95% CI 1.21 to 3.52), respectively), including after propensity matching (HR 1.58 (95% CI 1.01 to 2.48)). Conclusions AF is present in one in six patients with chronic≥moderate-to-severe AR and is associated with an increased risk of mortality even after adjusting for measures of LV systolic and diastolic function. There is a need for future prospective studies to validate these findings and evaluate AF as a potential trigger for early surgery.

ABSTRACT Background Incident atrial functional mitral regurgitation (AFMR) is associated with mortality. Transcatheter edge‐to‐edge repair (TEER) has shown effectiveness in improving MR and symptoms in AFMR, but previous studies lacked comparison to conservative management. We aimed to study the association of AFMR severity and mitral TEER with symptoms, heart failure hospitalizations (HFH) and all‐cause mortality in moderate/severe AFMR. Methods Consecutive adults with moderate/severe AFMR managed conservatively or with TEER 2010−2023 were identified retrospectively. To ensure similar technique in evaluation in the two groups, variables were obtained from the closest transthoracic echocardiogram before TEER in the TEER group. In addition to multivariable analysis, the association of TEER (vs. conservative management) with HFH and mortality was assessed using propensity‐score matched analyses; the propensity score was based on age, sex, EuroSCORE II, effective regurgitant orifice area, integrative MR severity, and NYHA class III/IV (vs. I/II). Results Among 230 patients with moderate/severe AFMR [mean age 77; 56% females], 46 were managed with TEER. Severe (vs. moderate) AFMR was independently associated with baseline NYHA class III/IV (multivariable OR 2.18 [95% CI 1.13−4.26]) and HFH [multivariable HR 2.75 (95% CI 1.25−6.03)] but not mortality ( p = 0.26). TEER improved MR to ≤ moderate in 93% but was not associated with lower HFH or death rates versus conservative management on multivariable or matched analysis. However, 1‐year NYHA improved more with TEER versus conservative management in patients with baseline NYHA class III/IV (62% vs. 27%, p = 0.03). Rhythm control was associated with improved survival (HR 0.38 [0.15−0.98]). Conclusions AFMR severity was associated with symptoms and HFH but not mortality. MR severity and NYHA class improved with TEER, but the association of TEER with HF hospitalizations or death remains unproven. Randomized studies are needed to evaluate the potential role of TEER and rhythm control on outcomes in AFMR.

Background: The relationship between vegetation characteristics in Staphylococcus aureus infective endocarditis (IE) and blood culture time to positivity (TTP) has not been investigated. This study evaluates the correlation between vegetation length and TTP in patients with S. aureus IE. Methods: A retrospective cohort study was conducted that included 164 definite cases S. aureus IE. Vegetation length was determined by transesophageal echocardiography (TEE), and TTP was measured in hours from the initial time of blood culture incubation to positivity. Correlations between vegetation characteristics and TTP were analyzed using Spearman’s rank correlation coefficient. Results: A modest but statistically significant negative correlation was observed between vegetation length and TTP (Spearman ρ = −0.18, p = 0.020), suggesting that larger vegetations were associated with shorter TTP. No significant correlations were found for other vegetation characteristics (e.g., vegetation mobility, location, or number) and TTP. Conclusions: Larger vegetation size in S. aureus IE was associated with shorter TTP. These findings highlight the importance of vegetation size in the pathophysiology of S. aureus IE and its role in bacteremia dynamics.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

Abstract Severe aortic valve regurgitation, if not timely treated, can significantly impact patients’ survival both for tricuspid aortic valve and bicuspid aortic valve patients, with the latter being significantly younger. Increased understanding of the root anatomy and its physiology has opened the way to techniques of aortic valve repair surgery. The techniques mainly relate to re-establishing a correct root and annular geometry and eliminating leaflet prolapse. These techniques are applied both in the presence of a dilated and normal root and are equally valid for tricuspid or bicuspid valve. Techniques for repairing a bicuspid valve might vary depending on the different valve phenotypes. Medium and long-term results appear favourable and potentially superior to those of prosthetic replacement in terms of valve-related complications and quality of life. Optimal surgical treatment, especially in younger and selected patients, should aim to avoid aortic valve replacement and its related complications.